Reply to: “Biejia-Ruangan compound and incidence of hepatocellular carcinoma”
Authors: Dong Ji, Lin Tan, Yongping Yang
Journal: Journal of Hepatology (2023)

Biejia-Ruangan compound and incidence of hepatocellular carcinomaJournal of HepatologyVol. 78Issue 4PreviewWe read with great interest the recent article “Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B” published in Journal of Hepatology.1 As Chinese hepatologists, we express our gratitude and appreciation to all the researchers in the current study which suggests that adding a traditional Chinese medicine Biejia-Ruangan compound (BRC) to entecavir showed superiority over entecavir alone in reducing the risk of hepatocellular carcinoma (HCC). Full-Text PDF Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis BJournal of HepatologyVol. 77Issue 6PreviewChronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial. Full-Text PDF Open Access We deeply appreciate Luo L et al. for their interest in our study.[1]Luo L. Yao X. Yang W. Biejia-Ruangan compound and incidence of hepatocellular carcinoma.J Hepatol. 2022 Nov; 16:S0168-8278 (Epub ahead of print. PMID: 36402448): 03305-0https://doi.org/10.1016/j.jhep.2022.11.012Abstract Full Text Full Text PDF Scopus (1) Google Scholar They raised concerns that: i) the incidence of hepatocellular carcinoma (HCC) was not included in the registration information of the randomized-controlled trial (RCT: NCT01965418); ii) it is hard to achieve an antitumor effect using anti-hepatic fibrosis drugs because liver fibrosis and development of HCC are two independent processes rather than a sequential series of events. Just as mentioned in the method section of our study, the present study was a long-term extension of our parent prospective RCT, rather than the RCT itself. In fact, the registered RCT was only the first part of our entire study, which focused on the synergistic enhancement of Biejia-Ruangan compound (BRC) on entecavir-induced regression of advanced fibrosis,[2]Rong G. Chen Y. Yu Z. Li Q. Bi J. Tan L. et al.Synergistic effect of biejia-ruangan on fibrosis regression in patients with chronic hepatitis B treated with entecavir: a multicenter, randomized, double-blind, placebo-controlled trial.J Infect Dis. 2022; 225: 1091-1099https://doi.org/10.1093/infdis/jiaa266Crossref PubMed Scopus (16) Google Scholar the long-term cohort study, for which development of HCC was a primary endpoint, was the second part. The detailed study protocol was published previously,[3]Qu J. Yu Z. Li Q. Chen Y. Xiang D. Tan L. et al.Blocking and reversing hepatic fibrosis in patients with chronic hepatitis B treated by traditional Chinese medicine (tablets of biejia ruangan or RGT): study protocol for a randomized controlled trial.Trials. 2014; 15: 438https://doi.org/10.1186/1745-6215-15-438Crossref PubMed Scopus (27) Google Scholar and the relevant study ID number (2013ZX10005002) was also noted in the registration information of NCT01965418. Statistically, the time-to-event analyses from the three populations (modified intention-to-treat [mITT], ITT, and per-protocol [PP]) were consistent, making our finding more solid and the conclusion more convincing. Furthermore, extension of a parent RCT has been used in many studies, for example.[4]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475https://doi.org/10.1016/S0140-6736(12)61425-1Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar,[5]Gupta A. Mackay J. Whitehouse A. Godec T. Collier T. Pocock S. et al.Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial.Lancet. 2018; 392: 1127-1137https://doi.org/10.1016/S0140-6736(18)31776-8Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Regarding risk factors for HCC, although some patients with hepatitis B develop HCC before they progress to cirrhosis, most researchers, as well as current consensus and guidelines, consider that cirrhosis is the strongest primary risk factor for HCC independent of liver disease etiology, such as EASL or AASLD HCC guidance, etc.6European Association for the Study of the LiverElectronic address: [email protected]; European association for the study of the liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 182-236https://doi.org/10.1016/j.jhep.2018.03.019Abstract Full Text Full Text PDF PubMed Scopus (4458) Google Scholar, 7Marrero J.A. Kulik L.M. Sirlin C.B. Zhu A.X. Finn R.S. Abecassis M.M. et al.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.Hepatology. 2018; 68: 723-750https://doi.org/10.1002/hep.29913Crossref PubMed Scopus (2239) Google Scholar, 8Llovet J.M. Kelley R.K. Villanueva A. Singal A.G. Pikarsky E. Roayaie S. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 6https://doi.org/10.1038/s41572-020-00240-3Crossref PubMed Scopus (1525) Google Scholar Nucleos(t)ide analogues (NAs) were designed to inhibit the replication of HBV, which is a risk factor for HCC. As we know, long-term suppression of HBV DNA using NAs in patients with CHB can reduce the incidence of HCC. So, logically, anti-fibrotic drugs could also reduce the risk of HCC development. In addition, BRC functions by boosting Qi, nourishing blood (transporters for Qi), softening hardness, dissipating abnormal masses, dissolving stasis, and eliminating pathogens, as described by traditional Chinese medicine (TCM) theories. The multi-pathway and multi-target pharmacological mechanisms make it possible to possess potent efficacy in preventing HCC. Previous studies have proved that the BRC can directly regulate the signaling pathways involved in HCC development, such as PI3K/AKT/NF-κB and the long non-coding RNA TUG1-microRNA-328-3p-SRSF9 mRNA axis.[9]Zhang Y. Mao X. Chen W. Guo X. Yu L. Jiang F. et al.A Discovery of clinically approved formula FBRP for repositioning to treat HCC by inhibiting PI3K/AKT/NF-κB activation.Mol Ther Nucleic Acids. 2020; 19: 890-904https://doi.org/10.1016/j.omtn.2019.12.023Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar By the way, drug repositioning is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication,[10]Pushpakom S. Iorio F. Eyers P.A. Escott K.J. Hopper S. Wells A. et al.Drug repurposing: progress, challenges and recommendations.Nat Rev Drug Discov. 2019; 18: 41-58https://doi.org/10.1038/nrd.2018.168Crossref PubMed Scopus (1877) Google Scholar which is promising in the field of TCM. Finally, our study can only provide evidence rather than detailed mechanisms. Nevertheless, this is one of the wonders of medical science, many unknowns are worth exploring, and they will eventually be elucidated and further enrich our understanding of life. This study was funded by the Ministry of Science and Technology of China (The National Key Projects Specialized on Infectious Disease, number 2013ZX10005002, 2018ZX10725506). The sponsor had no role in study design, data collection, data analysis and interpretation, or preparation of the manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. DJ and LT wrote the manuscript; YY provided guidance and proofread the manuscript; all authors revised and approved the final version. 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